Patent GB-744686-A (GB)
Title: Process for the manufacture of octahydroisoquinoline derivatives and acid addition salts thereof
Filed: 1953-06-10
Abstract: A process for the manufacture of octahydroisoquinoline derivatives comprises reacting N - methyl - b  - cyclohexen - (1) - yl - ethylamine with a substituted or unsubstituted phenylacetaldehyde or the bisulphite addition compound thereof, subjecting the unsaturated tertiary base obtained to the action of a strong mineral acid and heat, and if desired converting the octahydroisoquinoline derivative formed into an acid addition salt.  Alkoxy, benzyloxy and alkyl groups are mentioned as possible substituents in the phenylacetaldehyde (the benzyloxy group being converted to a hydroxy group in the cyclization step). The unsaturated tertiary base is believed to be a substituted or unsubstituted styryl-cyclohexenylethyl-methylamine.  (It absorbs two mols. of hydrogen and is converted to a saturated amine.)  As mineral acids for the cyclization 87 per cent phosphoric acid or 50 per cent sulphuric acid are specified.  Heating the unsaturated base with the acids yields substituted or unsubstituted 1-benzyl-2-methyl 1.2.3.4.5.6.7.8 - octahydroisoquinolines directly.  Treatment of the base with the acid in the cold gives as intermediates an isomeric substituted or unsubstituted 1 - benzyl - 2 - methyl - 1.2.3.4.6.7.8.9 - octahydroisoquinoline and a substituted or unsubstituted 1-benzyl-2-methyl-10-hydroxydecahydroisoquinoline which on heating with acid are transposed or dehydrated to the desired 1.2.3.4.5.6.7.8-octahydroisoquinoline derivative.  The products are of use in the preparation of N-methylmorphinanes.  In examples (1) phenylacetaldehyde and N-methyl-b -cyclohexen-(1)-yl-ethylamine are reacted in ether in the presence of anhydrous potassium carbonate. The tertiary base is heated with 87.6 per cent phosphoric acid to give 1-benzyl-2-methyl-1.2.3.4.5.6.7.8-octahydroisoquinoline from which the picrate and hydrochloride are prepared.  As an alternative (A) the unsaturated base is treated in the cold with 87 per cent phosphoric acid to give 1-benzyl - 2 - methyl - 1.2.3.4.6.7.8.9 - octahydroisoquinoline, which after isolation is heated with hydrochloric to give the 1-benzyl-2-methyl-1.2.3.4.5.6.7.8 - octahydroisoquinoline.  As a further alternative (B) the unsaturated tertiary base is treated in the cold with 50 per cent sulphuric acid to give 1-benzyl-2-methyl-10-hydroxy-decahydroisoquinoline, which after isolation is refluxed with hydrochloric acid to give the same product as in (A); (2) p-methoxyphenyl-acetaldehyde bisulphite addition compound and N - methyl - b  - cyclohexen - (1) - yl-ethyl-amine are reacted in ether with a little water in the presence of potassium carbonate.  Heating the unsaturated amine obtained with 50 per cent sulphuric acid gives 1-(41-methoxybenzyl) - 2 - methyl - 1.2.3.4.5.6.7.8-octahydro isoquinoline.  This product is also obtained if the tertiary amine is treated in the cold with phosphoric acid to give 1-(41-methoxy-benzyl)-2-methyl - 1.2.3.4.6.7.8.9 - octahydroisoquinoline and this latter compound is refluxed with 20 per cent hydrochloric acid; (3) 4-methoxy-3-benzyloxy - phenyl - acetaldehyde and N-methyl - b  - cyclohexen - (1) - yl - ethylamine are reacted in methanol and the unsaturated tertiary amine obtained is treated in the cold with 87 per cent phosphoric acid, and the product obtained is isolated (the benzyl group having been split off) and converted to 1 - (31 - hydroxy - 41-methoxy - benzyl) - 2 - methyl - 1.2.3.4.5.6.7.8-octahydro isoquinoline.